Many different compounds can block the behavioral effects of cocaine acutely. For example, dopamine antagonists, opioid antagonists and serotonin uptake inhibitors can all reduce cocaine self-administration. Kappa-opioid receptor agonists, which also acutely block the behavioral effects of cocaine, appear to have long-term effects as well. Days after the last of several injections of a kappa-opioid receptor agonist, the ability of cocaine to stimulate locomotor activity is still markedly reduced. This suggests that significant alterations in brain neurochemistry have occurred. Our previous studies suggest that dopaminergic changes alone cannot account for the decreased behavioral effects. Thus, it appears that other neurochemical systems are playing an important role in these long-term decreases in cocaine-stimulated activity. There are reciprocal interactions between cocaine and kappa-opioid receptors. In the other direction, chronic cocaine increases kappa-opioid receptors predominantly in serotonin rich brain regions. In addition, the upregulation of kappa-opioid receptors is not produced by selective dopamine uptake inhibitors. Together, these findings suggest that the bi-directional interactions between cocaine and kappa-opioid receptors are mediated by neurochemical systems other than dopamine, and our preliminary data all suggest that serotonin may play an important role in this regulation. The specific hypothesis of this proposal is that serotonin mediates the long-lasting regulation of cocaine-stimulated activity produced by kappa-opioid agonists, and that kappa-opioid agonist treatment produces long-term alterations in brain serotonin systems which greatly reduce the effects of cocaine on behavior. This hypothesis will be tested by studying the effects of altered serotonergic function on kappa-opioid receptor agonist regulation of cocaine-stimulated locomotor activity and cocaine self-administration. In addition, the effects of selective serotonin agonists and antagonists will be measured to determine which serotonin receptors are important in mediating this long-lasting effect. Since kappa-opioid receptor agonist treatment produces such marked effects on cocaine behaviors, and the effects continue long after the cessation of treatment, an understanding of the mechanism by which this occurs could lead to new avenues for the development of therapeutics for cocaine addiction.